In Patients with Aplastic Anaemia, Conditioning with Reduced Intensity Followed by Infusion of T-Cell Depleted Grafts Is Associated with Limited Transplant Related Morbidity and Universal Survival.
2007
Introduction: While the survival of patients receiving allogeneic stem cell transplantation for aplastic anaemia has improved significantly, a substantial number of patients develop extensive graft vs. host disease (GvHD), with the associated morbidity and mortality. T-cell depletion of grafts decreases the incidence and severity of GvHD but may result in greater risk of graft failure. Patients and methods: Between 2004 and 2007, seventeen patients with marrow aplasia were conditioned with fludarabine 30 mg/m 2 for 5 consecutive days (150 mg/m 2 ) followed by cyclophosphamide 120 mg/kg. In addition 2 (one with Fanconi’s anaemia) received busulfan 8 mg/kg. All had received more than 30 units of blood products and 2 had lymphocytotoxic antibodies that required HLA matched platelet transfusions. HLA identical sibling donors were mobilised with filgrastim (5–10 ug/kg) for 5 days and underwent large volume apheresis. Donor cells were quantitated and the CD34+ cell number determined. PBPC grafts were then incubated “in the bag” with alumtuzumab (1 mg/10 10 mononuclear cells) at 20°C for 30 minutes and infused without further processing. Patients commenced cyclosporin from day −1 and continued until day 90 post transplantation. End points were engraftment, OS, DFS, incidence and severity of GvHD. Results: Median age was 22 (7–49) years and 5/17 were females. Median CD34+ cell infused was 3.93 x 10 6 /kg, containing median of 22.2 x 1 4 /kg CFU-GM. The median “ex vivo” alumtuzumab dose employed was 10 mg (range 5–10 mg). There was universal engraftment and leukocytes reached 0.5 x 10 9 /L at a median of 14 days (8–17) post transplantation. Other than haematological suppression, the toxicity of the conditioning was limited to grade I–II intestinal side effects. Seven individuals did not develop pyrexia following infusion of the graft. No patient developed GvHD. Two subjects had CMV reactivation (pp65+) and responded to therapy with gancyclovir. Another two developed haemorrhagic cystitis due to BK virus. Donor-recipient sex mismatch was present in 8 instances and post transplant bone marrow karyotype analyisis showed that haematopoiesis was of donor’s origin in each case. One patient developed delayed graft failure 6 months post transplantation and had a satisfactory recovery following a second T- cell depleted transplant with similar conditioning. Another developed mixed chimerism at 8 months and received DLI. All patients survive at a median of 630 days (range 60–1433) with normal blood parameters. Conclusion: We conclude that purine analogues in combination with alkylators are a sufficiently intense immunosuppressive conditioning to allow successful engraftment of T-cell depleted PBPC grafts. Alumtuzumab “in the bag” led to excellent GvHD prophylaxis, leading to minimal morbidity of the procedure.
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